A Phase II Study of the TNF-α Inhibitor Etanercept and Thrice Weekly Rituximab in Relapsed CLL/SLL: Clinical Activity in the Absence of Del(17p13) Genomic Abnormalities.

Background: The monoclonal anti-CD20 antibody rituximab induces the death of chronic lymphocytic leukemia (CLL) in part through apoptosis. Tumor necrosis factor (TNF)-α and other cytokines up-regulate bcl-2 and other anti-apoptotic proteins, thereby inhibiting apoptosis. In addition, TNF-α may play a role in the cytokine release syndrome and infusion toxicity associated with monoclonal antibody therapy. Therefore, antagonists of TNF-α represent potential therapeutic agents that may decrease infusion toxicity and enhance rituximab-induced apoptosis.

Methods: We conducted a phase II trial of the TNF-α inhibitor etanercept in combination with rituximab in patients (pts) with relapsed CLL or small lymphocytic lymphoma (SLL), to determine if inhibition of TNF-α by etanercept increases the clinical activity of rituximab and reduces infusion toxicity. Pts received etanercept, 25 mg subcutaneously (SC) twice weekly during weeks 1–5, and rituximab, 375 mg/m² intravenously (IV) three times weekly during weeks 2–5. Stepped up dosing was utilized with the first two rituximab treatments.

Results: Thirty-six pts (25 male) with a median of 2 prior therapies (range 1–8) were enrolled; 23 pts had previously received rituximab. Therapy was generally well tolerated. Infusion reactions were mild and were not associated with severe adverse events. Fourteen pts experienced grade 1 (n=5) or grade 2 (n=9) infusion reactions. These infusion reactions extinguished with subsequent does of rituximab. Twelve pts developed grade 4 neutropenia, and neutropenic infections occurred in 4 pts, with 3 of these infections occurring during rapid CLL progression. Twelve pts developed grade 2 (n=10) or grade 3 (n=2) non-neutropenic infections. Nine of 32 evaluable pts (28%) achieved an NCI 96 response, with 8 partial responses (PR) and 1 complete response (CR). Median duration of response was 10 months. Eighteen pts had stable disease (SD), while 5 pts had progressive disease (PD). No responses were observed in 8 pts with del(17p13). In contrast, 9 of 24 pts (38%) without del(17p13) responded, including 3 pts with complex karyotypes. Sixteen pts with responsive or stable disease did not require additional treatment for CLL for 6 months after end of therapy, and the median treatment free survival for this group was 12 months. Eight of these 16 pts have not yet required other CLL therapy.

Conclusions: This study confirms our previous finding that single agent thrice weekly rituximab is ineffective in relapsed CLL with del(17p13) (Cancer Res 63: 36, 2003). The combination of rituximab and etanercept was well tolerated and demonstrated clinical activity in relapsed CLL pts without del(17p13). However, the addition of etanercept did not improve the clinical response rate beyond that expected with single agent thrice weekly rituximab.